Abstract In patients with SCD, pain results in an amalgam of negative physical and emotional consequences. A significant barrier to adequately address the pain of SCD is the insufficient information about underlying mechanisms affecting the variable degree and types of pain experienced by patients. Multiple biological and psychological factors (i.e., environmental stress) known so far to contribute to other pain conditions are under- studied in SCD. The arginine vasopressin receptor 1A is a 7-transmembrane domain G-protein polypeptide that is involved in stress and pain. The rs10877969 SNP in the receptor gene promoter (AVPR1A) is associated with aspects of acute pain and stress-related pain and the vasopressin system warrant further investigation into potential contributions to pain in SCD. I will utilize existing data for several vasopressin- related biological/psychosocial factors and quantitative sensory testing (QST) to investigate these mechanisms (and potential interactions) in SCD pain. I will also recruit a new study cohort of adults with SCD for a secondary, exploratory goal of performing an unbiased genome-wide search for SCD pain-related genetic modifiers in our large set of well-characterized subjects. I propose three specific aims: Aim 1. In an established data set from of 172 African Americans with SCD, I will perform statistical analysis: (a) To test for associations between AVPR1A genotype (rs10877969) and SCD experimental pain values (QST thermal and mechanical pain thresholds), which will determine whether pain thresholds vary based on AVPR1A genotype (i.e., a gene X environment interaction). Hypothesis: Thermal and mechanical pain thresholds will differ by genotype (the genotype will predict the QST pain thresholds). (b) To test whether the relationship between SCD clinical pain (API; Average Pain Intensity measured on 0-10 scale) and environmental stress (PSQ; Perceived Stress Questionnaire) is moderated by the rs10877969 genotype. Hypothesis: Genotype will influence the correlation between environmental stress and clinical pain. Aim 2. This work will also involve recruiting and characterizing a new cohort of 50 adults with SCD to study additional biological effectors of the vasopressin system for mechanistic insight: (a) To test for relationship of pain and stress phenotypes (including QST, API and PSQ) with AVPR1A gene expression (leukocyte AVPR1A mRNA levels measured by quantitative RT-PCR) and with promoter methylation. (b) To explore the variability in arginine vasopressin (surrogate copeptin) plasma concentration and associations with pain and stress. The data will be used to plan a future R01 study. Aim 3. As a pilot discovery study, to expand the search for genetic SCD pain modifiers, I will perform genome-wide association studies (GWAS) in the combined patient set (172+50) based on pain phenotype (API). Aims 1 and 2 will shed light on the role of the vasopressin system in SCD pain, and may provide insight for future studies into prediction and treatment of pain in this population, particularly stress-related. Exploratory Aim 3 may identify genes and pathways to investigate further in future studies of SCD pain.